The present invention relates to novel hydrates of erlotinib hydrochloride, a process for preparing them, pharmaceutical compositions thereof and their use as a medicament.
Erlotinib, chemically [6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine of formula 1
is a compound that inhibits the human epidermal growth factor receptor tyrosine kinase, also known as EGFR-TK, that is critical for growth of malignant cells. EGFR over expression is associated with disease progression, and reduced survival. Erlotinib acts by blocking tyrosine kinase activity of EGFR-TK, resulting in inhibition of signaling pathway, and decreased growth of malignant tumors. Erlotinib is thus useful for the treatment of proliferative disorders such as cancers in humans. Erlotinib is marketed as its hydrochloride salt.
WO 96/30347 (U.S. Pat. No. 5,747,498) discloses the preparation of erlotinib hydrochloride in example 20, by reaction of the base in chloroform/ether mixture with 1N HCl. It is only mentioned that it has a melting point of 228-230° C.
European patent application EP 1044969 discloses processes for the synthesis of erlotinib hydrochloride (examples 4, 7 and 9-11). In these processes, alcoholic solvents propan-2-ol, butan-1-ol, butan-2-ol and 2-methoxyethanol were used for the precipitation of the erlotinib hydrochloride by concentrated HCl. No data concerning the crystalline form of the hydrochloride compounds are disclosed except a melting point in example 4 of 226-229° C.
WO 01/34574 disclosed the existence of two polymorphic Forms of erlotinib hydrochloride which were designated as Form A and B. Form B is thermodynamically more stable than Form A. It may be prepared substantially free from polymorph A by crystallization of erlotinib hydrochloride Form A or of the mixture of polymorphs A and B from 2B-ethanol/water mixture. It is also mentioned in the application that example 20 of WO 96/30347 yields a mixture of Form A and B.
More recently WO 2004/072049 disclosed the existence of another polymorph of erlotinib hydrochloride, designated as Form E, which showed similar stability as Form B but with a higher solubility. It may be prepared by precipitation of erlotinib hydrochloride from trifluorotoluene.
The polymorphs disclosed above are anhydrous compounds, i.e. they do not comprise water in the crystalline lattice.